The long-term objectives of the proposed research are to gain a more complete view of oxidative stress and oxidative damage to oral streptococci and to use this information to develop effective antimicrobial for control of Dental plaque pathogenicity, primarily related to Dental caries. The Specific Aims of the project are the following. Specific Aim 1 is focused on defining in more detail adaptive responses of S. mutans to oxidative stress. The definition will include determinations of factors that induce the responses, including acidification, but particularly aerobic growth and exposure to sulfhydryl agents. Determination of the details of these responses, especially their physiologic regulation, will depend on genetic tools we already have developed, including mutants in genes for protective enzymes and for regulatory proteins. Specific Aim 2 involves basic studies of respiration of oral streptococci, especially mutans streptococci, including strains isolated directly from Dental plaque, and use of mono-organism and mixed-organism biofilms. Another part of the Aim is to define in more detail the major cell targets for oxidative damage, especially proteins, and to assess the energetics of protective mechanisms against oxidative stress, most of which require ATP, NADH and/or NADPH to function. Specific Aim 3 is focused on translational research with investigation of small molecules, such as zinc cations, benzimidazoles or other sulfhydryl-reacting agents, such as allicin, chelators, fluoride and other halogens, transition metal cations and oxidative antimicrobials. The research will be closely interdigitated with the basic studies of the first 2 Specific Aims with a view to using of basic information in developing agents or combinations of agents potent for enhancing oxidative damage to oral bacteria. The translational work will include studies with mono-organism and mixed biofilms and determinations of cell/biofilm permeabilities to, and retentiveness of, the test antimicrobials to help us evaluate their potentials for prophylactic and therapeutic use in the mouth. The research is directly related to public health, primarily the control of Dental caries, which is the most prevalent infectious disease among young people in the American population and a growing problem for older Americans. The work involves basic and applied studies Aimed at a better understanding of the biology of Dental plaque bacteria related especially to oxygen metabolism and damage caused by reactive oxygen species.